Project Summary: Project 3 Recent studies have begun to shed light on the complex interactions between the brain and body involved in Parkinson disease. Genetics, pathological studies, and model systems have highlighted the importance of cells of the myeloid lineage, particularly macrophages and other monocytes, in this brain/body interaction. In the brain, the resident myeloid cells are the microglia. Importantly, however, in several disease states it has been shown that circulating myeloid cells can infiltrate across the blood brain barrier in response to neuroinflammatory triggers and differentiate into macrophages and dendritic cells. Although the morphology of these ?invaders? may be similar to the resident microglia, their actions may be quite different, and they may be either pro-inflammatory, triggering neuron injury or death, or anti-inflammatory, contributing to resolution of local inflammation. While myeloid cells are conventionally dichotomized into M1 pro-inflammatory and M2 anti-inflammatory phenotypes, recent work has emphasized that these are extremes of a spectrum rather than discrete states. These activation states are the product of differential gene programs, and therefore, coding and non-coding RNA signatures are powerful tools for examining the functional states of myeloid cells. A key regulator of the activation of peripheral monocytes and their differentiation into pro-inflammatory macrophages and dendritic cells is microRNA 155 (miR-155). This project will employ recent advances in high-throughput genomic techniques to understand how peripheral myeloid cells function in PD. Based on our previous studies in mice, we will determine whether there is elevated miR-155 early in human disease. In addition, we will conduct transcriptional profiling of mRNAs and miRNAs in peripheral myeloid cells to identify important alterations in the gene programs regulating myeloid cell differentiation and activation, and assess the extent to which there is M1 polarization. All of the subjects recruited for this study will have early stage, untreated (?de novo?) Parkinson disease without chronic dopaminergic or anti-inflammatory treatment. This is a critically important patient population as it avoids issues arising from the effects of antiparkinsonian treatment. Together, these aims will provide an important test of the hypothesis that pro-inflammatory activation of peripheral myeloid cells occurs in early PD and that this activation is a critical part of the neurodegenerative process. It will also assist us in establishing the process and pathways needed for the future development of a Udall clinical core.